Pathogenesis of diseases like Alzheimer's and Parkinson's show mounting evidence of oxidative damage and inflammatory factors. Unfortunately, despite strong epidemiology and rationale, antioxidant and NSAID approaches to these age-related diseases have generally not been successful in the clinic. For example, vitamin E has failed in trials for Alzheimer's and heart disease prevention, while COX inhibitors have failed for Alzheimer treatment and been dropped for prevention efforts with traditional antioxidants (selenium, vitamin E, β-carotene), estrogens, and COX-2 inhibitors. The demographics of our aging population drive an urgent need for suitable alternatives for prevention and possible treatment of one or more of the chronic diseases of aging.
As a turmeric extract, curcumin is the yellow in yellow curries and is used as a food additive, for example, in yellow mustard. Like the “wonder drug” aspirin, which remains one of our few successful preventive agents, the long-term health potential of curcumin has a substantial history and a relatively well-established scientific basis. It has been identified as a major bioactive agent in an empirically developed system of traditional Indian and Chinese medicine.
Curcumin (diferulomethane) is not only a potent natural antioxidant and anti-inflammatory agent, acting on NFKB and AP-I regulated pro-inflammatory mediators including COX-2, iNOS, il-I and TNFα, but has multiple useful activities and has shown therapeutic potential in many pre-clinical culture and animal models for diseases, often related to aging. These include cancers (colon, prostate, breast, skin, leukemia, etc.) (Agarwal et al., 2003), prion disease (Caughey et al., 2003), atherosclerosis (Miguel et al., 2002; Ramaswami et al., 2004), stroke, CNS alcohol toxicity (Rajakrishnan et al., 1999), traumatic brain injury, Huntington's disease, Marie-Charcot Tooth, multiple sclerosis, and Alzheimer's disease.
Curcumin's structure, which includes both a lipohilic moiety and at least one hydroxyl group, resembles that of amyloid binding compounds. Amyloid dyes like Congo Red (CR) are known to bind via planar hydrophobic groups with appropriately spaced charge, and to suppress β-amyloid and other β-sheet-dependent peptide aggregation and toxicity. The Congo Red analogue, Chrysamine G, is more brain permeant and retains CR's amyloid binding properties. Curcumin shares the 19 angstrom CR spacing between its polar phenol groups; is readily brain permeant; and binds amyloid peptides, inhibiting their aggregation and toxicity in vitro. It has been discovered that curcumin effectively reduces amyloid accumulation in vivo in APP Tg mice. Because CR's anti-amyloid binding is generic and potentially relevant to other β-sheet intraneuronal aggregates including Huntington, a-synuclein, prions and tau, curcumin's anti-amyloid activity may be relevant beyond extracellular amyloid to intraneuronal aggregates. In fact, curcumin is one of the most effective anti-prion compounds ever tested in vitro, although it did not work in vivo with oral dosing of unstated formulation (Caughey et al., 2003). This raises the limitations of curcumin oral bioavailability.
The benefits of curcumin as a treatment for multiple diseases with aggregating amyloid proteins and other CAG repeat disorders are being established, and its efficacy in treating stroke, head trauma, metabolic syndrome, and many other conditions, including some forms of cancer and arthritis, as well as in promoting wound healing, is also beginning to be understood. All of these therapeutic applications are limited, however, because of poor intestinal absorption.
Although curcumin is an effective medication in multiple animal models for human diseases when given in chow at high doses (typically 2,000-5,000 ppm in diet in cancer trials), the current dogma is that it is so poorly bioavailable that it cannot be used for treatment outside the colon in humans. Curcumin is very hydrophobic and typically is not dissolved when delivered as a powder extract in common nutraceuticals. Most curcumin activities require 100-2,000 nanomolar (0.1-2 micromolar) levels in vitro, but current supplements result in negligible, low nanomolar blood levels (see Sharma et al., 2004). R. Sharma's group at Leicester has tried repeatedly and been unable to achieve significant blood levels beyond the low nanomolar range (Garcea G., Jones J. D., Singh R., Deunison A. R., Farmer P. B., Sharma R. A., Steward W. P., Gescher A. J., Berry D, P., “Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration,” Br J Cancer, 2004 Mar. 8; 90 (5); 1011-5.) They and others conclude that delivery of effective concentrations of oral curcumin to systemic tissues (outside the GI tract) is “probably not feasible.” Most of the literature supports this view, leading the NCI to focus on colon cancer.
Three factors limit curcumin absorption and need to be addressed: 1) rapid glucuronidation/sulfation of curcumin's phenolic hydroxyl groups and high “first pass” clearance; 2) curcumin is unstable in aqueous solution at pH 7 and above; and 3) curcumin is very hydrophobic and typically is not water soluble at acidic pH and when delivered as a dry powder in existing supplements. (Most of the curcumin is never absorbed and simply passes through the GI tract and is excreted.)
Solubilization is critical to prevent this, but curcumin requires pH 8.5 to dissolve completely. For this reason, cancer patients are taking huge doses, typically up to 8 gms a day. Diarrhea is a common side-effect. Garcea, G. et al. (2004) report that with patients taking 3.6 gms of curcumin a day (as a standard powder extract capsule supplied by Sabinsa Corporation), blood and liver levels achieved are negligible. They conclude that “[t]he results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.”
Curcumin is not soluble at acidic pH and breaks down when solubilized and diluted into water at neutral or alkaline pH (e.g., in the GI tract, after the small intestine), due to keto-enol transformations in the β-diketone bridge. In addition, curcumin is susceptible to rapid glucuronidation/sulfation. The major U.S. supplier, Sabinsa, has tried to make a more bioavailable form by adding Bioperine (piperine) to inhibit glucuronidation. Such an approach is flawed, however, because most glucuronidation takes place in the upper GI tract, where the pH is acidic, and curcumin is not completely dissolved until pH 8.5 and higher. Even worse, inhibiting glucuronidation can cause serious health risks. Glucuronidation is protective against many toxins and involved in the metabolism of commonly used drugs. Most elderly patients are on multiple drugs, at levels likely to be unsafely altered by inhibition of glucuronidation.
Curcuminoids are but one example of lipophilic compounds which have both a lipophilic moiety and at least one hydroxyl group. These compounds in general have problems of bioavailability as well as stability in an oral dosage form. Oral bioavailability requires stability, solubility and permeability of the active compound in the gut; however lipophilic compounds are generally not water soluble, and lipophilic compounds with hydroxyl groups may possess hydrolytic instability. Such solubility and instability issues are a substantial problem, both for bioavailability to the subject and for stability of the dosage form both in the gut and on the product shelf.
Dietary compounds and drugs which are water insoluble are found in a solid form in the gut. However, in order to absorb, a compound must either 1) dissolve in the water medium of the gut or 2) dissolve in the amphiphilic medium of the bile acid in the small intestine. A lipophilic compound containing one or more hydroxyl or acyl groups with a specific ratio of long-chain lipids allows for a greater level of colloidal dispersion.
Assuming a compound can achieve some level of solubility either in the aqueous or the lipid compartment of the gut, in both cases, the compound of interest is dispersed as an individual molecule in the medium, and exposed to oxidative (water) and hydrolytic (pH, enzymatic and microbial) conditions intended to break down and metabolize the compound, to excrete it from the body. In order to be absorbed intact, both the insolubility and instability issues must be addressed for a compound: addressing only one of these does not solve the problem.
Stability of a compound requires it to remain in a chemically electrostatically stable state in the medium in which it is found. (“Like dissolves like.”) In the gut, water of both very low and very high pH predominates. Each extreme induces a charge on an active compound (particularly those containing an unstable hydroxyl group that can unfavorable for stability of the compound. Further, hydroxyl radicals are highly reactive and undergo chemical reactions readily. Compounds that are mostly nonpolar, but which contain a polar hydroxyl group are prone to degradation in varying pH due to the loss or gain of charge on the hydroxyl group.
Many compositions in the art improve bioavailability by a marginal sum, which is repeated in the art. Nanoparticles, micelles, liposomes have all been developed but few have made commercial success. One reason is due to their instability in the gut. Small particles possess a high amount of surface area exposed to the acid and alkaline pH and enzymes of the gut.
It would therefore be advantageous if a composition or delivery device which improves the stability, solubility and permeability of certain types of biologically active compounds in the gut after oral consumption, resulting in parent (native) compound levels that are therapeutic (as opposed to inactive metabolites such as glucuronides), could be formulated.